Amide Chemistry Enables Redox Locking of Cyclic Disulfides for Polypeptide Assembly

A practical strategy in synthetic organic chemistry for shutting down temporarily the nucleophilicity of thiols is to exploit their redox properties by converting them into disulfides. The stability of such a thiol protection in reductive medium can be sensitive to microenvironmental changes, including chemical modifications occurring nearby. Although difficult to achieve, large shifts in disulfide stability might provide a practical mean for bringing selectivity in a reacting system comprising multiple thiol functionalities. Here we report that the stability of a cyclic disulfide increases dramatically upon acylation of an amino group placed in the vicinity of the S─S bond. The gain in stability is so pronounced that the amide bond formation acts as a redox lock. We describe the application of such a redox switch to the chemoselective assembly of polypeptides by thiol-based peptide ligation chemistries.